The weaver mutant mouse represents an animal model of genetically-induced dopaminergic cell loss in the central nervous system, with the nigrostriatal system exhibiting particular vulnerability. According to the proposed studies, we plan to investigate the functional neurochemical correlates of the anatomical deficit of the nigrostriatal systems, and to study the adaptive changes which take place when various neuronal systems attempt to compensate for the deleterious effects of the mutation. Specifically, those systems in the substantia nigra which utilize dopamine, substance P and cholecystokinin will be evaluated with regard to their functionality in the homozygous weaver relative to the wild-type control. Additionally, the peptide systems will also be investigated in other regions of the brain to determine if they have been affected (directly or indirectly) by the mutation. Finally, pharmacological studies will be conducted in order to determine if the neurochemical effects of the weaver mutation can be exacerbated and attenuated. The methodologies to be used in the proposed project involve a combination of in vitro and in vivo determinations of enzyme activities, uptake rates, release (basal and evoked), transmitter content (using high performance liquid chromatography and radioimmunoassay) and receptor binding. Additionally, various neuropharmacological techniques will also be employed. The experimental design will involve making direct comparisons of various parameters in the weaver mutant mouse with those in the control situation, at various stages of the disease process. Alterations detected during early stages of the disorder might provide important information about the primary defects whereas later-appearing changes might be indicative of secondary, and/or adaptive, compensatory phenomena. The results obtained from the proposed studies will provide a more fundamental understanding of the neurochemical events which accompany cell death in the central nervous system, and should provide much needed information which will be important for designing interventions which might be used in neurodegenerative disorders or aging.